Steroids azasteroids

Novel steroidal pyridazines are readily prepared from ADC compounds and steroidal A2,4-dienes,163 A14,1 -dienes,164 and A16,20-dienes.165 ADC compounds are also commonly used in the protection of the steroid 5,7-diene system (see Section V,A). These Diels-Alder adducts of steroidal dienes and azo dienophiles should not be confused with the so-called azasteroids, which are also prepared from ADC compounds. Cyclic ADC compounds such as the pyrazole-3,5-diones (7), and the diazaquinones 12 and 13 readily add to dienes to give bicyclic pyridazine derivatives,166168 and these reactions have been adapted to the synthesis of 5,10-diazasteroids (106).42 Similarly, the 13,14-diaza- (107) and 13,14,16-triazasteroid (108) ring systems have been prepared.169... 

Expansion of the D-ring of steroids to produce azasteroids is very common. Usually, the nitrogen is inserted between C(17) and the C ring and this kind of transformation was very popular in the search for new active pharmaceutical ingredients. Schonecker and colleagues performed the D ring expansion of 380 in-route to 17-aza-D-homosteroids (equation 152). 

The photo-addition of ethoxycarbonylnitrene on to unsaturated steroids and the photo-rearrangements of steroidal 4-azasteroidal 5-en-3-ones have been reviewed.248... 

Merck also patented a variety of steroidal SARMs. These are a variation of the 4-azasteroidal template of finasteride, a 5a-reductase inhibitor. Modifications at... 

Halogen substitution produces compounds with decreased activity except when inserted into positions 4 or 9 (e g., fluoxymesterone). Replacement of a carbon atom in position 2 by oxygen has produced the only clinically successful heterocyclic steroid among a number of azasteroids and oxasteroids. Some of the 2-oxasteroids are potent anabolic agents. 

Important, naturally occurring derivatives are quoted in brackets. Sapogenins and steroid alcohols contain hetero atoms linked with the side chain and ring D the cardenolides and bufadienolides possess an imsaturated 5 or 6-ring lactone instead of the chain at C l as well as cis C/D fusion. In synthetic steroid chemistry, one frequently encounters derivatives which have been formed by shortening, lengtheniug, opening, transformation or introduction of hetero atoms they are named after the fundamental skeleton with terms like nor-, homo-, seco-, abeo-, azasteroids etc. Reference must be made to the specialist literature on steroid chemistry for detailed information (e. g., [55, 108]). 

Heterocyclic Steroids - Much synthetic work continues to be published in this area. Two non-basic aza steroids, 13-aza-17-ketones, were prepared with the stated purpose of testing a hypothesis that the usual lack of hormonal activity of azasteroids is due to an Inability of basic steroids to penetrate cell membranes. However, no biological information was given.Some 15-aza-, 15,l6-diaza-, and 11,15,16-triazasterolds ° were synthesized. The former two types are reported to have anti-bacterial activity, whereas 17a-aza-0-homosteroids are inactive.The acetylation of one inactive 173-hydroxy-4-azasteroid was shown to confer anti-bacterial activity to the compound, but this effect was not general. The syntheses of a 5,10-diazasterold and of an A,B-indolo-steroid (14) were also reported. The successful preparations of 2-oxa,... 

Syntheses of Azasteroids, Qxasteroids, and Thia-steroids. The AB route has been used to effect the total syn-... 

The route for the synthesis of steroid analogs with heteroatoms in positions 4 and 6 (Scheme 41) is analogous to that described in Schemes 38 and 39 for the carbocyclic steroids. The starting material used for the synthesis of 4-azasteroids was the quinolone (420) which with the performance... 

Syntheses by this route are conveniently grouped in accordance with the classes of steroid compounds synthesized. They are used mainly for two purposes to obtain estrogenic hormones and, from these, 19-norsteroids, on the one hand, and to obtain derivatives of vitamin D, on the other hand. In the latter case, obviously, the necessity for cyclization with the formation of ring B is absent, and the ACD fragments obtained are the final products of the synthesis. Total syntheses of 8- and 9-azasteroids are also considered individually in this section. 

Syntheses of Azasteroids. Syntheses of 6-, 8-, and 9-aza-steroids have been carried out by the method of building up the steroid skeleton considered in this section (Schemes 92 and 93). 

Since all the most important natural steroids have already been obtained by total synthesis, each reaction in the steroid series can in fact now be regarded as a "formal total synthesis" of the products formed in it. Such a situation requires the drawing of the clearest possible boundaries between the partial and total synthesis of steroids. In our opinion, the term total synthesis can be applied only to those investigations in which the construction of the side chains distinguishing the classes of steroid compounds was connected organically with the construction of the steroid skeleton (as is the case in the syntheses of aldosterone and conessine). From this point of view, it must be regarded as incorrect to describe as total syntheses, for example, the syntheses of equilin, diosgenin, and tomatidine these syntheses deliberately start from natural steroids and must be classified as partial syntheses. In view of what has been said, in this book our main attention is devoted to the construction of the steroid skeleton and not to the introduction of side chains. The broad development of the chemistry of the heterocyclic steroids has made it necessary also to consider the main methods for the total synthesis of azasteroids, oxasteroids, and thiasteroids. 

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